PRENATAL COUNSELING

• Extraneous DNA contamination remains a problem with molecular technology, despite application of intracytoplasmic sperm injection
  
• Only partial amplification of the allele may occur, or allele “drop-out” may be present; both of these phenomena can cause false-negative results
  
• Error can occur dually: 1) Presumably unaffected embryos that are, indeed, affected are transferred and 2) actually normal embryos that have been interpreted incorrectly as abnormal are discarded
  
• The rate of misdiagnosis (false-negative results) ranges from 2% (with autosomal-recessive disorders) to 10% (with autosomal-dominant disorders), although this rate can be lessened with the use of linked markers.
  

PGD for investigating balanced chromosome rearrangements

These rearrangements represent another type of genetic abnormality in which PGD can reduce the likelihood of a conception that carries a specific genetic abnormality.

When one parent carries a balanced chromosome translocation, fluorescence in-situ hybridization (FISH) can be applied to assess the segregation of at-risk chromosomes in a single blastomere cell. In this technique, fluorescence-labeled DNA probes, selected for specificity to the translocation in question, are applied to the single cell fixed on a glass slide. Copies of the DNA segment and, by inference, the chromosomal segment in question are assessed by quantification of the sites of positive fluorescence.

Because translocation carriers are, theoretically, at high risk of transmission of an unbalanced segregant to the blastomere, as many as 10 blastomeres will often be screened until one or two are deemed normal for the FISH probes in question. When implantation does succeed after FISH analysis for a chromosome rearrangement, however, the pregnancy loss rate is lower and the likelihood of a live birth is higher.

Again, in-depth consultation is needed before PGD

Whether PGD is planned for investigating a single-gene disorder or a chromosome translocation, detailed consultation with the woman or the couple is important. This effort should include not only genetic counseling about inheritance, the natural history of the disorder in question, and other options for avoiding the transmission of the disorder—in addition, additional time should be spent describing:

• risks associated with IVF procedures and embryo biopsy (and with extended culture, if needed)
  
• technical limitations of the particular testing that is being considered
  
• options for prenatal testing during a pregnancy
  
• the possibility that embryos suitable for transfer will not be found (and that, potentially, erroneously tested normal embryos will not be transferred)
  
• disposition of embryos in which test results are inconclusive.
  

PGS for women at increased risk of aneuploidy isn’t supported by evidence; consider it investigational

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Mersereau JE, Pergament E, Zhang X, Milad MP. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90:1287–1289.

Aneuploidy contributes to pregnancy loss among women as they become older. Theoretically, avoiding aneuploid pregnancy among embryos transferred during IVF cycles—in older women and in women experiencing multiple pregnancy losses and failed IVF cycles—was expected to increase the implantation rate and decrease the rate of pregnancy loss.

This hypothesis was supported, at first, by observational trials. But at least one randomized study, by Staessen and colleagues,¹ failed to demonstrate that PGS is beneficial in women of advanced maternal age.

Now, a large multicenter, randomized, double-blind, controlled trial conducted by Mastenbroek and co-workers provides further evidence that PGS does not increase the rate of pregnancy and, in fact, significantly reduces that rate among women of advanced maternal age.

The Mastenbroek study compared outcomes among 206 women who had PGS and 202 women who did not. Both groups were matched for maternal age older than 35 years. Blastomeres were analyzed for eight chromosomes, including those known to be highly associated with miscarriage (1, 16, 17, 13, 18, and 21; X and Y).

Among women who underwent PGS, 25% had an ongoing pregnancy of at least 12 weeks’ gestation, compared with 37% of unscreened women. A similar higher rate of live birth was seen among unscreened women (35%, versus 24% in the PGS group).

Mastenbroek’s results are comparable to what was reported from an earlier randomized trial of PGS,¹ in which the implantation rate as the primary outcome among women who had PGS and among controls was not significantly different. Contributors to 1) the lack of success of PGS and 2) the apparent detriment of PGS to the ongoing pregnancy rate include:

• potential for damage to the embryo at biopsy
  
• limitations imposed by FISH technology on the number of probes that can be accurately assessed technically
  
• a growing knowledge that a significant percentage of embryos are chromosomal mosaics at this stage—a phenomenon that likely results in nontransfer of embryos that have the potential for developing karyotypically normally.